Benzoxadiazoles and benzothiadiazoles

ABSTRACT

Compounds of formula I, ##STR1## wherein X is oxygen or sulphur, and R 1  -R 6  are various substituents. The compounds are useful for treating coronary insufficiency, intermittent claudication, cerebrovascular insults, spasms in muscles and hypertension.

This is a division of application Ser. No. 359,751, filed Mar. 19, 1982,now issued as U.S. Pat. No. 4,466,972, which in turn is a continuationof application Ser. No. 173,305, filed July 29, 1980, now abandoned,which is turn is a continuation-in-part of Ser. No. 101,591, filed Dec.10, 1979, now abandoned, which in turn is a continuation-in-part of Ser.No. 915,585, filed June 15, 1978, now abandoned.

The present invention relates to benzoxadiazoles and benzothiadiazoleshaving a 4-dihydropyridine moiety.

The present invention provides in particular compounds of formula I,##STR2## wherein R₁ is hydrogen, alkyl(C₁₋₆), hydroxyalkyl(C₂₋₆),alkoxyalkyl(C₃₋₆), alkenyl(C₃₋₆), alkinyl(C₃₋₆), cycloalkyl(C₃₋₇),cycloalkylalkyl(C₄₋₈), phenylalkyl(C₇₋₉) or phenylalkenyl(C₉₋₁₂), thephenyl ring being unsubstituted or mono-, di- or trisubstitutedindependently by halogen, hydroxy, alkyl(C₁₋₄) or alkoxy (C₁₋₄),

R₂ and R₅, independently, are hydrogen, alkyl(C₁₋₆), phenylalkyl(C₇₋₁₀),cycloalkyl(C₃₋₇) or cycloalkylalkyl(C₄₋₈),

R₃ and R₄, independently are CN, COR₇, COOR₇, S(O)_(n) R₇ or ##STR3##wherein n is 0, 1 or 2,

R₇ is alkyl(C₁₋₆), alkenyl(C₃₋₆), alkinyl(C₃₋₆), cycloalkyl(C₃₋₇),cycloalkylalkyl(C₄₋₈), hydroxyalkyl(C₂₋₆), alkoxyalkyl(C₃₋₆),hydroxyalkoxyalkyl(C₄₋₈), aminoalkyl(C₂₋₆), alkyl(C₁₋₄)aminoalkyl(C₂₋₆),di[alkyl(C₁₋₄)]aminoalkyl, phenyl, phenylalkyl(C₇₋₁₀), a 5- or6-membered heterocyclic ring containing one heteroatom selected fromnitrogen, oxygen or sulphur and may contain additionally 1, 2 or 3 ringnitrogen atoms, or alkyl(C₁₋₄) substituted by a 5- or 6-memberedheterocyclic ring containing one heteroatom selected from nitrogen,oxygen or sulphur and may contain additionally 1, 2 or 3 ring nitrogenatoms,

A is alkylene(C₁₋₆),

R₈ and R₉, independently, are alkyl(C₁₋₆), alkenyl or alkinyl(C₃₋₆),cycloalkyl(C₃₋₇), cycloalkylalkyl(C₄₋₈), hydroxyalkyl(C₂₋₆),alkoxyalkyl(C₃₋₆), hydroxyalkoxyalkyl(C₄₋₈), aminoalkyl(C₂₋₆),alkyl(C₁₋₄)aminoalkyl(C₂₋₆), di[alkyl(C₁₋₄)]aminoalkyl, phenyl,phenylalkyl(C₇₋₁₀), or

R₈ and R₉ together with the nitrogen atom form a 5-, 6- or 7-memberedheterocyclic ring, which may contain a further heteromember selectedfrom oxygen, sulphur and a group ═N--R₁₀, wherein R₁₀ is alkyl (C₁₋₄),

R₆ is hydrogen, halogen, alkyl(C₁₋₄), alkoxy(C₁₋₄), alkylthio(C₁₋₄),alkylsulfonyl(C₁₋₄), trifluoromethyl, nitro, hydroxy, azido, amino,alkyl(C₁₋₄)amino, di[alkyl(C₁₋₄)]amino, alkanoyl(C₁₋₅)amino,carbalkoxy(C₂₋₅), aminocarbonyl, trifluoromethoxy, cyano, sulfamyl,alkyl(C₁₋₄)sulfamyl or di[alkyl(C₁₋₄)]sulfamyl, and

X is oxygen or sulphur.

One group of compounds comprises compounds of formula I as definedabove, with the proviso that, when

R₁ is hydrogen, alkyl(C₁₋₆), alkenyl(C₃₋₆), alkinyl(C₃₋₆),cycloalkyl(C₃₋₇), cycloalkylalkyl(C₄₋₈), phenylalkyl(C₇₋₉) orphenylalkenyl(C₉₋₁₂), the phenylring being unsubstituted or mono-, di-or tri-substituted independently by halogen, hydroxy, alkyl(C₁₋₄) oralkoxy(C₁₋₄),

R₂ and R₅, independently, are hydrogen or alkyl(C₁₋₆),

R₆ is hydrogen, halogen, alkyl(C₁₋₄), alkoxy(C₁₋₄), alkylthio(C₁₋₄),alkylsulfonyl(C₁₋₄), trifluoromethyl, nitro or hydroxy, and

X is oxygen or sulphur, then at least one of the substituents R₃ and R₄is other than COR₇ ^(I), wherein R₇ ^(I) is alkyl(C₁₋₆), alkenyl(C₃₋₆),alkinyl(C₃₋₆), cycloalkyl(C₃₋₇), cycloalkylalkyl(C₄₋₈), and is otherthan COOR₇ ^(II), wherein R₇ ^(II) is alkyl(C₁₋₆), alkenyl (C₃₋₆),alkinyl(C₃₋₆), cycloalkyl(C₃₋₇), cycloalkylalkyl(C₄₋₈),hydroxyalkyl(C₂₋₆), alkoxyalkyl(C₃₋₆) or hydroxyalkoxyalkyl(C₄₋₈).

In any of the above radicals alkyl of 1 to 6 carbon atoms is preferablyof 1 to 4 carbon atoms, especially of 1 to 2 carbon atoms. Any alkyl,alkoxy, alkylthio or alkylsulfonyl radical of 1 to 4 carbon atoms ispreferably of 1 to 2 carbon atoms. The hydroxy, alkoxy, hydroxyalkoxy,amino or alkylamino group of the hydroxyalkyl, alkoxyalkyl,hydroxyalkoxyalkyl, aminoalkyl or alkylaminoalkyl moiety in COOR₇ ispreferably not attached to the α-carbon atom and is preferably attachedto the distal terminal carbon atom. Any hydroxyalkyl, alkoxyalkyl,hydroxyalkoxyalkyl, aminoalkyl or alkylaminoalkyl radical preferably hasan ethylene or propylene moiety substituted by hydroxy, alkoxy,hydroxyalkoxy, amino or alkylamino respectively. The alkyl moiety ofcycloalkylalkyl is conveniently methyl. Halogen means fluorine, chlorineor bromine and is especially chlorine. Cycloalkyl or the cycloalkylmoiety of cycloalkylalkyl is conveniently cyclopropyl or cyclopentyl orcyclohexyl. The multiple bond of alkenyl, alkinyl or phenylalkenyl in R₁or COOR₇ is preferably not in the α,β position. Alkenyl or alkinylpreferably has 3 to 5 carbon atoms. Alkenyl is conveniently allyl or2-methylallyl. Alkinyl is conveniently propinyl. Phenylalkenylpreferably has the trans-configuration and is for example cinnamyl. WhenR₁ is optionally substituted phenylalkyl, the phenyl group is preferablyunsubstituted. When the phenyl group is di- or tri-substituted,preferably the substituents are the same.

When R₇ is alkyl, this is preferably branched. When R₇ contains aheterocyclic ring this may be for example furyl, thienyl, pyrrolyl,thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl,oxadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl,pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, morpholinyl ortriazinyl.

When R₈ and R₉ together with the nitrogen atom to which they are bound,form a heterocyclic ring, this is preferably saturated and may be forexample pyrrolidine, piperidine, piperazine, N-alkylpiperazine,morpholine, azepane, diazepane or N-alkyl-diazepane.

R₁ is conveniently hydrogen. R₂ is conveniently identical to R₅. R₂ isconveniently alkyl. R₃ and/or R₄ is conveniently COOR₇ or ##STR4## R₇ isconveniently alkyl, preferably branched or alkoxyalkyl, where the alkoxymoiety is preferably branched. A is conveniently ethylene. R₈ and R₉ areconveniently alkyl or phenylalkyl.

The present invention also provides a process for the production of acompound of formula I as defined above, comprising replacing the moiety--HC═Y in a compound of formula II, ##STR5## wherein R₆ and X are asdefined above, and --HC═Y is

(i) formyl,

(ii) a radical of formula ##STR6## or (iii) a radical of formula##STR7## wherein Z and Z' are independently oxygen or NR₁, and

R₁ to R₅ are as defined above,

by a moiety of formula III, ##STR8## wherein R₁ to R₅ are as definedabove.

The process may be effected in conventional manner for analogousdihydropyridine syntheses, e.g. according to Hantzsch. When the moiety--HC═Y is formyl and when it is desired to produce a compound of formulaI, wherein R₂ is identical to R₅ and R₃ is identical to R₄, it isconvenient to react a compound of formula II with a compound of formulaIV,

    R.sub.5 CO--CH.sub.2 --R.sub.4                             IV

wherein R₄ and R₅ are as defined above, in the presence of a compound offormula V,

    H.sub.2 NR.sub.1                                           V

wherein R₁ is as defined above.

Preferably at least 2 moles of a compound of formula IV per mole of acompound of formula II are present. Alternatively a compound of formulaII may be reacted with a compound of formula VI,

    R.sub.5 --C(NH--R.sub.1)═CH--R.sub.4                   VI

wherein R₁, R₄ and R₅ are as defined above.

Preferably at least 2 moles of a compound of formula VI per mole of acompound of formula II are present. Preferably also R₁ is hydrogen.

When the moiety --HC═Y is formyl and preferably when it is desired toproduce a compound of formula I wherein R₂ is different to R₅ and/or R₃is different to R₄, it is also possible to react such a compound offormula II with a compound of formula IV and a compound of formula VII,

    R.sub.2 --C(NH--R.sub.1)═CH--R.sub.3                   VII

wherein R₂, R₁ and R₃ are as defined above.

It will be appreciated that a compound of formula VI may be formed as anintermediate during the reaction of a compound of formula IV and acompound of formula V. A compound of formula II, wherein -HC═Y is aradical ii) or iii), may be formed as an intermediate in the abovereactions. They may however be produced by different processes.

Alternatively or particularly for the production of a compound offormula I, wherein R₂ is different to R₅ and/or R₃ is different to R₄,it is convenient to react a compound of formula II, wherein the moiety--HC═Y is a radical ii) with a compound of formula IV or VI, and whereappropriate, with a compound of formula V. A compound of formula II,wherein the moiety --HC═Y is a radical iii) may be an intermediate.

In the above reactions it is possible in certain instances when R₂, R₃,R₄ and R₅ are not identical that more than one isomer of formula I maybe formed. If so these may be separated in conventional manner, e.g. bycolumn or thin layer chromatography.

When the starting material is a compound of formula II, wherein --HC═Yis a radical iii), the reaction is a ring cyclisation. When Z and Z' areboth oxygen, then an amine of formula V should be present.

However, all the above reactions may be effected under the sameconditions.

The reaction may be effected conveniently in solution. A suitablesolvent is water, ethanol, dioxane, dimethyl formamide, dimethylsulphoxide, pyridine or glacial acetic acid. Suitable reactiontemperatures may be from 20° to 160° C., preferably from 60° to 120° C.

Insofar as the production of starting materials is not particularlydescribed these compounds are known or may be produced in analogousmanner to known compounds.

The basic compounds of formula I may be converted into acid additionsalt forms in conventional manner and vice versa. Suitable acids aree.g. maleic acid, oxalic acid, methanesulphonic acid, hydrochloric acidand hydrobromic acid.

The present invention provides a group of compounds of formula Ia,##STR9## wherein R₁ is hydrogen, alkyl of 1 to 6 carbon atoms, alkenylor alkinyl of 3 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms,cycloalkylalkyl of 4 to 8 carbon atoms, phenylalkyl of 7 to 9 carbonatoms or phenylalkenyl of 9 to 12 carbon atoms, the phenyl ring beingunsubstituted or mono-, di- or trisubstituted independently by halogen,hydroxy or alkyl or alkoxy of 1 to 4 carbon atoms,

R₂ and R₅, independently are hydrogen or alkyl of 1 to 6 carbon atoms,

R₃ ^(I) and R₄ ^(I), independently, are alkyl of 1 to 6 carbon atoms,alkenyl or alkinyl of 3 to 6 carbon atoms, cycloalkyl of 3 to 7 carbonatoms, cycloalkylalkyl of 4 to 8 carbon atoms, alkoxy of 1 to 6 carbonatoms, hydroxyalkoxy of 2 to 6 carbon atoms, alkoxyalkoxy of 3 to 6carbon atoms, hydroxyalkoxyalkoxy of 4 to 8 carbon atoms, alkenyloxy oralkinyloxy of 3 to 6 carbon atoms, cycloalkyloxy of 3 to 7 carbon atomsor cycloalkylalkoxy of 4 to 8 carbon atoms,

R₆ is hydrogen, halogen, alkyl or alkoxy or alkylthio or alkylsulfonyl,each of 1 to 4 carbon atoms, trifluoromethyl, nitro or hydroxy, and

X is oxygen or sulphur.

In any of the above radicals alkyl of 1 to 6 carbon atoms is preferablyof 1 to 4 carbon atoms, especially of 1 or 2 carbon atoms. Any alkyl,alkoxy, alkylthio or alkylsulfonyl radical of 1 to 4 carbon atoms ispreferably of 1 or 2 carbon atoms. The alkyl moiety of cycloalkylalkylor cycloalkylalkoxy is conveniently methyl. Halogen means fluorine,chlorine or bromine and is especially chlorine. Cycloalkyl or thecycloalkyl moiety of cycloalkylalkyl or cycloalkylalkoxy is convenientlycyclopropyl or cyclopentyl or cyclohexyl. The multiple bond of alkenyl,alkinyl, alkenyloxy, alkinyloxy or phenylalkenyl is preferably not inthe α, β position. Alkenyl, alkenyloxy, alkinyl or alkinyloxy preferablyhas 3 to 5 carbon atoms. Alkenyl or the alkenyl moiety of alkenyloxy isconveniently allyl or 2-methylallyl. Alkinyl or the alkinyl moiety ofalkinyloxy is conveniently propinyl. Phenylalkenyl preferably has thetrans-configuration and is for example cinnamyl. When R₁ is optionallysubstituted phenylalkyl, the phenyl group is preferably unsubstituted.When the phenyl group is di- or tri-substituted, preferably thesubstituents are the same. When R₃ ^(I) and/or R₄ ^(I) is alkoxy, thisis preferably ethoxy or methoxy. When R₃ ^(I) and/or R₄ ^(I) isalkoxyalkoxy or hydroxyalkoxyalkoxy, preferably the carbon chain betweenthe two ether oxygen atoms is of 2 carbon atoms. The hydroxy group ofhydroxyalkoxy or of hydroxyalkoxyalkoxy is preferably not attached tothe carbon atom attached to an ether oxygen atom. R₁ is preferablyhydrogen. R₂ is conveniently identical to R₅. R₂ and/or R₅ is preferablymethyl. R₃ ^(I) and/or R₄ ^(I) is preferably alkoxy or alkoxyalkoxy,especially n-butyloxyethoxy. R₆ is conveniently halogen, alkyl oralkoxy, or especially hydrogen. R₆ is conveniently adjacent to thedihydropyridine moiety which in turn is conveniently in the 4-position.

In the following examples all temperatures are in degrees Centigrade andare uncorrected.

EXAMPLE 14-(2,1,3-Benzoxadiazol-4-yl)-2,6-dimethyl-1,4-dihydro-pyridine-3,5-dicarboxylicacid diethyl ester

3.2 g of 2,1,3-benzoxadiazole-4-aldehyde, 5.7 g of acetoacetic acidethyl ester, 2.5 ml of concentrated ammonia and 10 ml of ethanol arerefluxed for 6 hours. The mixture is subsequently evaporated and theresidual oil is chromatographed on silica gel with chloroform/aceticacid ethyl ester (9:1) to yield the title compound. The product isrecrystallised from toluene, m.p. 153°-155°.

By using the process described in Example 1, and corresponding startingcompounds, e.g. a compound of formula II, wherein --HC═Y is a radical i)and compounds of formula IV and V, and for Examples 18 and 19 a compoundof formula II, wherein --HC═Y is a radical ii), wherein Z is oxygen anda compound of formula VI, the following compounds of formula Ia may beobtained, wherein y indicates the position of the dihydropyridinemoiety:

    __________________________________________________________________________    Example                                                                            R.sub.1                                                                         R.sub.2                                                                          R.sub.3.sup.I                                                                       R.sub.4.sup.I                                                                       R.sub.5                                                                          R.sub.6                                                                            X y m.p.                                        __________________________________________________________________________     2   H CH.sub.3                                                                         OC.sub.2 H.sub.5                                                                    OC.sub.2 H.sub.5                                                                    CH.sub.3                                                                         H    S 4 146-148                                      3   H CH.sub.3                                                                         OC(CH.sub.3).sub.3                                                                  OC(CH.sub.3).sub.3                                                                  CH.sub.3                                                                         H    S 4 193-199                                      4   H CH.sub.3                                                                         OCH.sub.3                                                                           OCH.sub.3                                                                           CH.sub.3                                                                         7-Cl O 4 207-211                                      5   H CH.sub.3                                                                         OCH.sub.3                                                                           OCH.sub.3                                                                           CH.sub.3                                                                         H    S 4 215-216                                      6   H CH.sub.3                                                                         OC.sub.2 H.sub.5                                                                    OC.sub.2 H.sub.5                                                                    CH.sub.3                                                                         5-OCH.sub.3                                                                        S 4 201-203                                      7   H CH.sub.3                                                                         OC.sub.2 H.sub.5                                                                    OC.sub.2 H.sub.5                                                                    CH.sub.3                                                                         7-Cl S 4 135-155                                      8   H CH.sub.3                                                                         OC.sub.2 H.sub.5                                                                    OC.sub.2 H.sub.5                                                                    CH.sub.3                                                                         H    S 5 152-153                                      9   H CH.sub.3                                                                         OC.sub.2 H.sub.5                                                                    OC.sub.2 H.sub.5                                                                    CH.sub.3                                                                         4-Cl S 5 198-200                                     10   H CH.sub.3                                                                         C(CH.sub.3 ).sub.3                                                                  C(CH.sub.3).sub.3                                                                   CH.sub.3                                                                         H    S 4                                             11   H CH.sub.3                                                                         CH.sub.3                                                                            CH.sub.3                                                                            CH.sub.3                                                                         7-Cl O 4                                             12   H CH.sub.3                                                                         CH.sub.3                                                                            CH.sub.3                                                                            CH.sub.3                                                                         H    S 4 225-228                                     13   H CH.sub.3                                                                         C.sub.2 H.sub.5                                                                     C.sub.2 H.sub.5                                                                     CH.sub.3                                                                         5-OCH.sub.3                                                                        S 4                                             14   H CH.sub.3                                                                         C.sub.2 H.sub.5                                                                     C.sub.2 H.sub.5                                                                     CH.sub.3                                                                         7-Cl S 4                                             15   H CH.sub.3                                                                         C.sub.2 H.sub.5                                                                     C.sub.2 H.sub.5                                                                     CH.sub.3                                                                         H    S 5                                             16   H CH.sub.3                                                                         C.sub.2 H.sub.5                                                                     C.sub.2 H.sub.5                                                                     CH.sub.3                                                                         4-Cl S 5                                             17   H CH.sub.3                                                                         CH.sub.3                                                                            CH.sub.3                                                                            CH.sub.3                                                                         H    O 4 218-222                                     18   H CH.sub.3                                                                         CH.sub.3                                                                            OC.sub.2 H.sub.5                                                                    CH.sub.3                                                                         H    O 4 186-188                                     19   H CH.sub.3                                                                         CH.sub.3                                                                            OC.sub.2 H.sub.5                                                                    CH.sub.3                                                                         H    S 4 146-148                                     __________________________________________________________________________

EXAMPLE 204-(2,1,3-Benzoxadiazol-4-yl)-2,6-dimethyl-1,4-dihydro-3-methoxycarbonyl-pyridine-5-carboxylic acid isobutyl ester

3 g of 2,1,3-benzoxadiazole-4-aldehyde, 3.2 g of acetoacetic acidisobutyl ester, 2.3 g β-aminocrotonic acid methyl ester and 10 ml ofethanol are stirred under reflux for 3 hours. The mixture issubsequently evaporated and the residue is chromatographed on silica gelwith chloroform/acetic acid ethyl ester (8:1) to yield the titlecompound. The product is recrystallised from diisopropyl ether andmethylcyclohexane, m.p. 148°-158°.

By using the process described in Example 1, and corresponding startingcompounds, e.g. a compound of formula II, wherein --HC═Y is a radical(i) and compounds of formula IV and V, and for Examples 23, 24 and 27 to36 a compound of formula II, wherein --HC═Y is a radical (ii), wherein Zis oxygen and a compound of formula VI, the following compounds offormula Ia, wherein R₂ and R₅ are each methyl and R₆ is hydrogen, may beobtained, wherein y indicates the position of the dihydropyridinemoiety:

    __________________________________________________________________________    Comp.                                                                             R.sub.3.sup.I                                                                            R.sub.4.sup.I                                                                          R.sub.1                                                                           y X m.p.                                          __________________________________________________________________________    21  OCH.sub.3  OCH.sub.3                                                                              H   4 O 215-221                                       22  OC.sub.2 H.sub.5                                                                         OC.sub.2 H.sub.5                                                                       H   5 O 173-174                                       23  OCH.sub.2 CH(CH.sub.3).sub.2                                                             OC.sub.2 H.sub.5                                                                       H   4 S 85-95                                         24  OCH.sub.2 CH(CH.sub.3).sub.2                                                             OC.sub.2 H.sub.5                                                                       H   4 O   145-146.5                                   25  OC(CH.sub.3).sub.3                                                                       OC(CH.sub.3).sub.3                                                                     H   4 O 207-210                                       26  OCH.sub.2 CH(CH.sub.3).sub.2                                                             OCH.sub.2 CH(CH.sub.3).sub.2                                                           H   4 O 135.5-137                                     27  O(CH.sub.2).sub.2 OC.sub.2 H.sub.5                                                       OC.sub.2 H.sub.5                                                                       H   4 O 126-128                                       28  O(CH.sub.2).sub.2 OC.sub.2 H.sub.5                                                       OC.sub.2 H.sub.5                                                                       H   4 S oil                                           29  O(CH.sub.2).sub.2 OC.sub.2 H.sub.5                                                       OC.sub.2 H.sub.5                                                                       H   5 S 72-78                                         30  OCH(CH.sub.3).sub.2                                                                      OCH.sub.3                                                                              H   4 O 168-170                                       31  O(CH.sub.2).sub.2 OCH.sub.3                                                              OCH.sub.3                                                                              H   4 O 151-153                                       32  O(CH.sub.2).sub.2 OCH(CH.sub.3).sub.2                                                    OCH.sub.3                                                                              H   4 O 114-120                                       33  O(CH.sub.2).sub.2 OC.sub.2 H.sub.5                                                       OCH.sub.3                                                                              H   4 O 140-147                                       34                                                                                 ##STR10## OCH.sub.3                                                                              H   4 O 156-163                                       35  O(CH.sub.2).sub.2 OCH.sub.3                                                              OCH(CH.sub.3).sub.2                                                                    H   4 O 119                                           36  OCH.sub.3  OC.sub.2 H.sub.5                                                                       H   4 O 159                                           37  OC.sub.2 H.sub.5                                                                         OC.sub.2 H.sub.5                                                                       CH.sub.3                                                                          4 O 106                                           38  OC.sub.2 H.sub.5                                                                         OC.sub.2 H.sub.5                                                                       n-C.sub.3 H.sub.7                                                                 4 O  99                                           __________________________________________________________________________

In addition from a compound of formula II, wherein --HC═Y is a radicalii), wherein Z is oxygen and a compound of formula VI there may be madethe following compounds of formula I, wherein y indicates the positionof the dihydropyridine moiety:

    __________________________________________________________________________    Ex.                                                                              R.sub.1                                                                         R.sub.2                                                                          R.sub.3      R.sub.4    R.sub.5                                                                          R.sub.6                                                                         X y m.p.                                 __________________________________________________________________________    39 H CH.sub.3                                                                         CN           COOi-Bu    CH.sub.3                                                                         H O 4 123-124.5                            40 H CH.sub.3                                                                         COOC.sub.2 H.sub.5                                                                         SO.sub.2 CH.sub.3                                                                        CH.sub.3                                                                         H O 4 204-205                              41 H CH.sub.3                                                                         CN           COOC.sub.2 H.sub.5                                                                       CH.sub.3                                                                         H O 4 167-177                              42 H CH.sub.3                                                                         CN           COOC.sub.2 H.sub.5                                                                       CH.sub.3                                                                         H S 4 187-190                              43 H CH.sub.3                                                                         CN           COOCH.sub.2 CH(CH.sub.3).sub.2                                                           CH.sub.3                                                                         H S 4 166-171                              44 H CH.sub.3                                                                         COOCH.sub.3  COC.sub.6 H.sub.5                                                                        CH.sub.3                                                                         H O 4 192-201                              45 H CH.sub.3                                                                          ##STR11##   COOC.sub.2 H.sub.5                                                                       CH.sub.3                                                                         H O 4 180-184**                            46 H CH.sub.3                                                                          ##STR12##   COOC.sub.2 H.sub.5                                                                       CH.sub.3                                                                         H S 4 173-175**                            47 H CH.sub.3                                                                         COO(CH.sub.2).sub.2 N(CH.sub.3).sub.2                                                      COO(CH.sub.2).sub.2 N(CH.sub.3).sub.2                                                    CH.sub.3                                                                         H O 4 188-191*                                                                      fumarate                             48 H CH.sub.3                                                                         COO(CH.sub.2).sub.2 N(CH.sub.3).sub.2                                                      COO(CH.sub.2).sub.2 N(CH.sub.3).sub.2                                                    CH.sub.3                                                                         H S 4 156-159                                                                       fumarate                             49 H CH.sub.3                                                                         COO(CH.sub.2).sub.2 N(CH.sub.3).sub.2                                                      COOC.sub.2 H.sub.5                                                                       CH.sub.3                                                                         H O 4                                      50 H CH.sub.3                                                                         COO(CH.sub.2).sub.2 N(CH.sub.3).sub.2                                                      COOC.sub.2 H.sub.5                                                                       CH.sub.3                                                                         H S 4 166-176                                                                       hydrogen-                                                                     furmarate                            51 H CH.sub.3                                                                          ##STR13##   COOC.sub.2 H.sub.5                                                                       CH.sub.3                                                                         H S 5 oil                                  52 H CH.sub.3                                                                          ##STR14##   COOC.sub.2 H.sub. 5                                                                      CH.sub.3                                                                         H O 5 oil                                  53 H CH.sub.3                                                                          ##STR15##   COOCH.sub.3                                                                              CH.sub.3                                                                         H O 4 182-195**                            54 H                                                                                ##STR16##                                                                       COOC.sub.2 H.sub.5                                                                         COOC.sub.2 H.sub.5                                                                       CH.sub.3                                                                         H O 4 97-99                                55 H                                                                                ##STR17##                                                                       COOCH.sub.3  COOCH.sub.3                                                                              CH.sub.3                                                                         H O 4 160-163                              56 H                                                                                ##STR18##                                                                       COOCH.sub.3  COOCH.sub.3                                                                               ##STR19##                                                                       H O 4 118-120                              57 H                                                                                ##STR20##                                                                       COOC.sub.2 H.sub.5                                                                         COOC.sub.2 H.sub.5                                                                        ##STR21##                                                                       H O 4 110-112                              58 H CH.sub.3                                                                         COO(CH.sub.2).sub.2C.sub.6 H.sub.5                                                         COOCH.sub.3                                                                              CH.sub.3                                                                         H O 4 156                                  59 H CH.sub.3                                                                         COOCH.sub.3  COOCH.sub.2 C.sub.6 H.sub.5                                                              CH.sub.3                                                                         H O 4 131-136                              __________________________________________________________________________     *decomposition                                                                **hydrochloride                                                          

      Ex. R.sub.1 R.sub.2 R.sub.3 R.sub.4 R.sub.5 R.sub.6 y X       a CH.sub.3 H COnC.sub.6 H.sub.13 COnC.sub.6 H.sub.13 H 4-C.sub.2     H.sub.5 5 S b nC.sub.6 H.sub.13 n-C.sub.6 H.sub.13 COCH.sub.2CHCHC.sub.2     H.sub.5 COCH.sub.2 CHCHC.sub.2 H.sub.5 n-C.sub.6 H.sub.13 6-SC.sub.2     H.sub.5 5 S  c C.sub.2      H.sub.5CHCHCH.sub.2 H     ##STR22##      ##STR23##      H 7-CH.sub.3 5 S      d     ##STR24##      H      ##STR25##      ##STR26##      H 4-NO.sub.2 5 S      e     ##STR27##      H COOCH.sub.2 OC.sub.2 H.sub.5 COOCH.sub.2 OC.sub.2 H.sub.5 H 4-OH 5 S     f      ##STR28##      H COO(CH.sub.2).sub.2 OCH.sub.2 OH COO(CH.sub.2).sub.2 OCH.sub.2 OH H H     5 S      g     ##STR29##      H COOCH.sub.2 CHCHC.sub.2 H.sub.5 COOCH.sub.2CHCHC.sub.2 H.sub.5 H H 5     S      h     ##STR30##      H      ##STR31##      ##STR32##      H H 5 S      i     ##STR33##      H      ##STR34##      ##STR35##      H H 5 S      j     ##STR36##      H COO(CH.sub.2).sub.4 OH COO(CH.sub.2).sub.4 OH H 7-SO.sub.2 C.sub.2     H.sub.5 5 S  k C.sub.2      H.sub.5CCCH.sub.2 H     ##STR37##      ##STR38##      H 7-CF.sub.3 5 S  l nC.sub.6 H.sub.13 nC.sub.6 H.sub.13 COCH.sub. 2CCH     COCH.sub.2CCH n-C.sub.6 H.sub.13 6-SC.sub.2 H.sub.13 5 S      m     ##STR39##      H      ##STR40##      ##STR41##      H 4-NO.sub.2 5 S      n     ##STR42##      H      ##STR43##      ##STR44##      H H 5 S      o     ##STR45##      H COOCH.sub.2CCC.sub.2 H.sub.5 COOCH.sub.2CCC.sub.2 H.sub.5 H H 5 S  p      ##STR46##      C.sub.4      H.sub.9     ##STR47##      CO(CH.sub.2).sub.3 NHC.sub.3 H.sub.7 H 7-OC.sub. 3 H.sub.7 5 O  q     CH.sub.2 CCC.sub.2      H.sub.5 H     ##STR48##      ##STR49##      H 7-NHCOC.sub.4 H.sub.9 5 O      r     ##STR50##      H      ##STR51##      SiC.sub.3 H.sub.7 H 6-nC.sub.6 H.sub.13 5 S      s     ##STR52##      H      ##STR53##      SO.sub.2 C.sub.4 H.sub.9 H 7-SO.sub.2 C.sub.2 H.sub.5 5 S      t     ##STR54##      H SO.sub.2 (CH.sub.2).sub.3 OC.sub.2 H.sub.5 SO.sub.2 (CH.sub.2).sub.2     C.sub.6 H.sub.5 H 6-NO.sub.2 5 S  u CH.sub.3 H COCH.sub.2      CHCH     ##STR55##      H      ##STR56##      5 S  v C.sub.6 H.sub.5 CH.sub.2 (CH.sub.2).sub.3 C.sub.6 H.sub.5      ##STR57##      COO(CH.sub.2).sub.3      OCH.sub.3     ##STR58##      7-OCF.sub.3 5 S  w CH.sub.2CHCHC.sub.2      H.sub.5     ##STR59##      ##STR60##      ##STR61##      C.sub.4 H.sub.9 6-N.sub.3 4 S      x     ##STR62##      H SCH.sub.2CCH COO(CH.sub.2).sub.5NHC.sub. 2 H.sub.5 H 7-F  y C.sub.6     H.sub.5 H      ##STR63##      ##STR64##      C.sub.3 H.sub.7 7-COONC.sub.6 H.sub.13 5 S      z     ##STR65##      i-C.sub.3 H.sub.7 SO.sub.2 CH.sub.2 OC.sub.3      H.sub.7     ##STR66##      H 6-OH 4 S      aa     ##STR67##      H S(CH.sub.2).sub.3      O(CH.sub.2).sub.2OH     ##STR68##      H 6-CF.sub.3 5 S  ab nC.sub.6 H.sub.13 nC.sub.6      H.sub.13     ##STR69##      ##STR70##      nC.sub.6 H.sub.13 7-NHiC.sub.4 H.sub.9 5 S      ac     ##STR71##      (CH.sub.2).sub.3 C.sub.6      H.sub.5     ##STR72##      ##STR73##      (CH.sub.2).sub.3 C.sub.6 H.sub.5 H 5 S      ad     ##STR74##      H SO.sub.2 (CH.sub.2).sub.3 NHC.sub.3 H.sub.7 SO.sub.2 (CH.sub.2).sub.3     NHC.sub.3      H.sub.7 H     ##STR75##      5 O      ae     ##STR76##      H      ##STR77##      SO.sub.2 (CH.sub.2).sub.2 C.sub.3      H.sub.7 7-NO.sub.2 5 S

In addition from a compound of formula II, wherein --HC═Y is a radicalii), wherein Z is oxygen and a compound of formula VI there may be madethe following compounds of formula Ia wherein X=S and the1,4-dihydropyridine moiety is in the 5-position and R₁ to R₆ arerespectively: ##STR78##

    __________________________________________________________________________      R.sub.1 R.sub.2                                                                              R.sub.3  R.sub.4     R.sub.5                                                                              R.sub.6                                                                            y X                         __________________________________________________________________________    (p)                                                                             C.sub.4 H.sub.8 CCH                                                                   CH.sub.3                                                                                      COOCH.sub.2 CCH                                                                           CH.sub.3                                                                             7-OCF.sub.3                                                                        5 S                         (q)                                                                             CCC.sub.2 H.sub.5                                                                     H                                                                                     ##STR79##                                                                              ##STR80##  C.sub.2 H.sub.5                                                                      6-CN 4 S                         (r)                                                                              ##STR81##                                                                             ##STR82##                                                                           SOC.sub.2 H.sub.4 OC.sub.2 H.sub.5                                                     COCH.sub.2CHCH.sub.2                                                                       ##STR83##                                                                           7-nC.sub.4 H.sub.9                                                                 4 O                         (s)                                                                              ##STR84##                                                                            C.sub.2 H.sub.5                                                                      CN       CO(CH.sub.2).sub.2 N(C.sub.3 H.sub.7).sub.2                                               C.sub.2 H.sub.5                                                                      6-Br 5 S                         (t)                                                                              ##STR85##                                                                            C.sub.2 H.sub.5                                                                      CN       COOCH.sub.2CCH                                                                            CH.sub.3                                                                             6-Br 5 S                         __________________________________________________________________________

By using the process described in Example 1, and corresponding startingcompounds, e.g. a compound of formula II, wherein --HC═Y is a radical(i) and compounds of formula IV and V, and for Examples 61, 62 and 65 to74 a compound of formula II, wherein --HC═Y is a radical ii), wherein Zis oxygen and a compound of formula VI, the following compounds offormula I, wherein R₂ and R₅ are each methyl and R₆ is hydrogen, may beobtained, wherein y indicates the position of the dihydropyridine moietyand R₃ and R₄ are COR₇ ^(I) and COR₇ ^(II) respectively:

    ______________________________________                                        Comp. R.sub.7.sup.I R.sub.7.sup.II                                                                            R.sub.1                                                                             y   X                                   ______________________________________                                        60    C.sub.2 H.sub.5                                                                             C.sub.2 H.sub.5                                                                           H     5   O                                   61    CH.sub.2 CH(CH.sub.3).sub.2                                                                 C.sub.2 H.sub.5                                                                           H     4   S                                   62    CH.sub.2 CH(CH.sub.3).sub.2                                                                 C.sub.2 H.sub.5                                                                           H     4   O                                   63    C(CH.sub.3).sub.3                                                                           C(CH.sub.3).sub.3                                                                         H     4   O                                   64    CH.sub.2 CH(CH.sub.3).sub.2                                                                 CH.sub.2 CH(CH.sub.3).sub.2                                                               H     4   O                                   65    (CH.sub.2).sub.2 OC.sub.2 H.sub.5                                                           C.sub.2 H.sub.5                                                                           H     4   O                                   66    (CH.sub.2).sub.2 OC.sub.2 H.sub.5                                                           C.sub.2 H.sub.5                                                                           H     4   S                                   67    (CH.sub.2).sub.2 OC.sub.2 H.sub.5                                                           C.sub.2 H.sub.5                                                                           H     5   S                                   68    CH(CH.sub.3).sub.2                                                                          CH.sub.3    H     4   O                                   69    (CH.sub.2).sub.2 OCH.sub.3                                                                  CH.sub.3    H     4   O                                   70    (CH.sub.2).sub.2 OCH(CH.sub.3).sub.2                                                        CH.sub.3    H     4   O                                   71    (CH.sub.2).sub.2 OC.sub.2 H.sub.5                                                           CH.sub.3    H     4   O                                   72                                                                                   ##STR86##    CH.sub.3    H     4   O                                   73    (CH.sub.2).sub.2 OCH.sub.3                                                                  CH(CH.sub.3).sub.2                                                                        H     4   O                                   74    CH.sub.3      C.sub.2 H.sub.5                                                                           H     4   O                                   75    C.sub.2 H.sub.5                                                                             C.sub.2 H.sub.5                                                                           CH.sub.3                                                                            4   O                                   76    C.sub.2 H.sub.5                                                                             C.sub.2 H.sub.5                                                                           n-C.sub.3 H.sub.7                                                                   4   O                                   ______________________________________                                    

The compounds of formula I exhibit pharmacological activity. Inparticular, they lead to a dilation of the coronary vessels asdemonstrated by the results of tests measuring the blood flow to themyocardium of an anaesthetised cat by means of the microsphere method(Rudolph A. M. and Heymann M. S.: Circulation Research 21, 163, 1967)upon administration of from 30 to 50 μg/kg i.v. or of from 50 to 150μg/kg i.d. of the active substance.

The compounds of formula I also possess a favourable effect againstangina pectoris, as shown by the increase of the coronary flow of ananesthetised cat upon administration of the active substance.

The compounds of formula I are useful in the treatment of coronaryinsufficiency. For the above-mentioned use the dosage will, of course,vary depending on the compound employed, mode of administration andtherapy desired. However, in general satisfactory results are obtainedwith a daily dosage of 0.01 to 10 mg/kg animal body weight, convenientlygiven in divided doses 2 to 4 times a day or in sustained release form.For the larger mammal, the total daily dosage is in the range from about5 to 100 mg, and dosage forms suitable for oral administration comprisefrom about 1.25 mg to about 50 mg of the compounds admixed with a solidor a liquid pharmaceutical carrier or diluent.

The compounds of formula I increase the blood flow to limbs, e.g. legmusculature, as can be shown by means of the microsphere method on theanaesthetised cat upon administration of from 30 to 50 μg/kg i.v. orfrom 50 to 150 μg/kg i.d. of the compounds.

The compounds of formula I are therefore useful for treatment ofintermittent claudication and other peripheral disturbances of bloodflow to limb muscles. For the above-mentioned use the dosage will, ofcourse, vary depending on the compound employed, mode of administrationand therapy desired. However, in general satisfactory results areobtained with a daily dosage of 0.01 to 10 mg/kg animal body weight,conveniently given in divided doses 2 to 4 times a day or in sustainedrelease form. For the larger mammal, the total daily dosage is in therange from about 5 to 100 mg, and dosage forms suitable for oraladministration comprise from about 1.25 mg to about 50 mg of thecompounds admixed with a solid or a liquid pharmaceutical carrier ordiluent.

The compounds of formula I increase cerebral blood flow, as can be shownby means of the microsphere method on the anesthetised cat uponadministration of from 30 to 50 μg/kg i.v. or from 50 to 150 μg/kg i.d.of the compounds.

The compounds of formula I are therefore useful in the treatment ofcerebrovascular insults (accidents). For the above-mentioned use thedosage will, of course, vary depending on the compound employed, mode ofadministration and therapy desired. However, in general satisfactoryresults are obtained with a daily dosage of 0.01 to 10 mg/kg animal bodyweight, conveniently given in divided doses 2 to 4 times a day or insustained release form. For the larger mammal, the total daily dosage isin the range from about 5 to 100 mg, and dosage forms suitable for oraladministration comprise from about 1.25 mg to about 50 mg of thecompounds admixed with a solid or a liquid pharmaceutical carrier ordiluent.

The compounds of formula I possess calciumantagonistic activity, asindicated in standard tests, for example by an inhibition of a calciuminduced contraction of isolated dog coronary arteries suspended in adepolarizing solution at concentration of 10⁻¹⁰ to 10⁻⁸ M of thecompounds according to the principles of Godfraind and Kaba, Brit. J.Pharm. 36, 549-560, 1969. The compounds are therefore useful asspasmolytic agents, for the treatment of spasms in muscles. For theabove-mentioned use the dosage will of course, vary depending on thecompound employed, mode of administration and therapy desired. However,in general satisfactory results are obtained with a daily dosage of 0.01to 10 mg/kg animal body weight, conveniently given in divided doses 2 to4 times a day or in sustained release form. For the larger mammal, thetotal daily dosage is in the range from about 5 to 100 mg, and dosageforms suitable for oral administration comprise from about 1.25 mg toabout 50 mg of the compounds admixed with a solid or a liquidpharmaceutical carrier or diluent.

Additionally, the compounds of formula I exhibit antihypertensiveactivity, as indicated by a blood pressure lowering activity in standardtests.

For example, the compounds exhibit a blood pressure lowering effect inthe Grollman rat test [see A. Grollman, Proc. Soc. Expt. Biol. and Med.57, 104 (1944)] on s.c. administration of from 0.1 to 10 mg/kg animalbody weight of the compounds.

The compounds are therefore useful as anti-hypertensive agents. For thisuse the dosage will, of course, vary depending on the compound employed,mode of administration and therapy desired. However, in general,satisfactory results are obtained with a daily dosage of from 0.5 to 50mg/kg animal body weight, conveniently given in divided doses 2 to 4times a day or in sustained release form. For the larger mammal, thetotal daily dosage is in the range form about 5 to about 1000 mg, e.g.30 to 1000 mg, and dosage forms suitable for oral administrationcomprise from about 1.25 mg to about 500 mg of the compounds admixedwith a solid or liquid pharmaceutical carrier or diluent.

A compound of formula I may be administered in free base form.Alternatively any sufficiently basic compound of formula I, e.g. thosecompounds wherein R₃ or R₄ contain an amino moiety, may be administeredin pharmaceutically acceptable acid addition salt form. Such acidaddition salt forms exhibit the same order of activity as the free baseforms. The present invention also provides a pharmaceutical compositioncomprising a compound of formula I in association with a pharmaceuticalcarrier or diluent. Such compositions may be prepared by conventionaltechniques to be in conventional forms, for example capsules or tablets.

The compounds of Examples 1, 20, 24, 30-38, 45, 53 and 59 areparticularly interesting. The coronary insufficiency, the intermittentclaudication, the cerebrovascular insufficiency and the spasmolyticactivities are the preferred utilities for compounds of formula I.

In a group of compounds of formula Ia R₁ is hydrogen, alkyl, alkenyl,cycloalkyl of 3 to 6 carbon atoms, phenylalkyl, or phenylalkenyl; thephenyl ring being unsubstituted or substituted by one, two or threesubstituents chosen form one or two halogen radicals, one or two alkylgroups of 1 to 4 carbon atoms, one to three alkoxy groups of 1 to 4carbon atoms; R₃ ^(I) and R₄ ^(I), independently, are alkyl, alkenyl,cycloalkyl of 3 to 6 carbon atoms, alkoxy, hydroxyalkoxy of 2 to 6carbon atoms, alkoxyalkoxy of 3 to 6 carbon atoms, hydroxyalkoxyalkoxyof 4 to 8 carbon atoms, alkenyloxy, or cycloalkyloxy of 3 to 6 carbonatoms, and R₆ is other than alkylsulfonyl.

Conveniently R₁ is hydrogen, R₂ and R₅ are each alkyl, especiallymethyl, R₃ ^(I) and R₄ ^(I) are each alkoxy, especially ethoxy, R₆ ishydrogen or halogen, especially chlorine, especially in the 4 position,the dihydropyridine moiety is in the 4 or 5 position, and X is S.

Alternatively conveniently R₁ is hydrogen, R₂ and R₅ are each alkyl,especially methyl, R₃ ^(I) and R₄ ^(I) are alkyl or alkoxy, especiallymethyl, ethyl, tert. butyl, methoxy, ethoxy or tert.butyloxy, R₆ ishydrogen or halogen, especially chlorine, or alkoxy, especially methoxy,the dihydropyridine moiety is in the 4 or 5 position and R₆ is in the 4,5 or 7 position.

In one group of compounds of formula I

R₁ is hydrogen, alkyl(C₁₋₆), hydroxyalkyl(C₂₋₆), alkoxyalkyl(C₃₋₆),alkenyl(C₃₋₆), alkinyl(C₃₋₆), cycloalkyl(C₃₋₇), cycloalkylalkyl(C₄₋₈),phenylalkyl(C₇₋₉) or phenylalkenyl(C₉₋₁₂), the phenyl ring beingunsubstituted or mono-, di- or trisubstituted independently by halogen,hydroxy, alkyl(C₁₋₄) or alkoxy (C₁₋₄),

R₂ and R₅, independently, are hydrogen, alkyl(C₁₋₆) orphenylalkyl(C₇₋₁₀),

R₃ and R₄, independently are CN, COR₇, COOR₇ or S(O)_(n) R₇,

wherein

n is 0, 1 or 2,

R₇ is alkyl(C₁₋₆), alkenyl(C₃₋₆), alkinyl(C₃₋₆), cycloalkyl(C₃₋₇),cycloalkylalkyl(C₄₋₈), hydroxyalkyl (C₂₋₆), alkoxyalkyl(C₃₋₆),hydroxyalkoxyalkyl(C₄₋₈), aminoalkyl(C₂₋₆), alkyl(C₁₋₄)aminoalkyl(C₂₋₆),phenyl, phenylalkyl(C₇₋₁₀), a 5- or 6-membered heterocyclic ringcontaining one heteroatom selected from nitrogen, oxygen or sulphur, oralkyl (C₁₋₄) substituted by a 5- or 6-membered heterocyclic ringcontaining one heteroatom selected from nitrogen, oxygen or sulphur,

R₆ is hydrogen, halogen, alkyl(C₁₋₄), alkoxy(C₁₋₄), alkylthio(C₁₋₄),alkylsulfonyl(C₁₋₄), trifluoromethyl, nitro, hydroxy, azido, amino,alkyl(C₁₋₄)amino, alkanoyl(C₁₋₅)amino, carbalkoxy(C₂₋₄), aminocarbonyl,trifluoromethoxy, cyano, sulfamyl, alkyl(C₁₋₄)sulfamyl ordi[alkyl(C₁₋₄)]sulfamyl, and

X is oxygen or sulphur, with the proviso that when R₁ is hydrogen,alkyl(C₁₋₆), alkenyl(C₃₋₆), alkinyl (C₃₋₆), cycloalkyl(C₃₋₇),cycloalkylalkyl(C₄₋₈), phenylalkyl(C₇₋₉) or phenylalkenyl(C₉₋₁₂), thephenylring being unsubstituted or mono-, di- or trisubstitutedindependently by halogen, hydroxy, alkyl(C₁₋₄) or alkoxy(C₁₋₄),

R₂ and R₅, independently, are hydrogen or alkyl(C₁₋₄),

R₆ is hydrogen, halogen, alkyl(C₁₋₄), alkoxy(C₁₋₄), alkylthio(C₁₋₄),alkylsulfonyl(C₁₋₄), trifluoromethyl, nitro or hydroxy, and

X is oxygen or sulphur, then at least one of the substituents R₃ and R₄is other than COR₇ ^(I), wherein R₇ ^(I) is alkyl(C₁₋₆), alkenyl(C₃₋₆),alkinyl(C₃₋₆), cycloalkyl(C₃₋₇), cycloalkylalkyl(C₄₋₈), and is otherthan COOR₇ ^(II), wherein R₇ ^(II) is alkyl(C₁₋₆), alkenyl (C₃₋₆),alkinyl(C₃₋₆), cycloalkyl(C₃₋₇), cycloalkylalkyl(C₄₋₈),hydroxyalkyl(C₂₋₆), alkoxyalkyl(C₃₋₆) or hydroxyalkoxyalkyl(C₄₋₈).

In another group of compounds of formula I

R₁ is hydrogen, alkyl(C₁₋₆), hydroxyalkyl(C₂₋₆), alkoxyalkyl(C₃₋₆),alkenyl(C₃₋₆), alkinyl(C₃₋₆), cycloalkyl(C₃₋₇), cycloalkylalkyl(C₄₋₈),phenylalkyl(C₇₋₉) or phenylalkenyl(C₉₋₁₂), the phenyl ring beingunsubstituted or mono-, di- or trisubstituted independently by halogen,hydroxy, alkyl(C₁₋₄) or alkoxy (C₁₋₄),

R₂ and R₅, independently, are hydrogen, alkyl(C₁₋₆) orphenylalkyl(C₇₋₁₀),

R₃ is ##STR87## and R₄ is CN, COR₇, COOR₇, S(O)_(n) R₇ or ##STR88##wherein n is 2,

R₇ is alkyl(C₁₋₆), alkenyl(C₃₋₆), alkinyl(C₃₋₆), cycloalkyl(C₃₋₇),cycloalkylalkyl(C₄₋₈), hydroxyalkyl(C₂₋₆), alkoxyalkyl(C₃₋₆),hydroxyalkoxyalkyl(C₄₋₈), aminoalkyl(C₂₋₆), alkyl(C₁₋₄)aminoalkyl(C₂₋₆),phenyl or phenylalkyl(C₇₋₁₀),

A is alkylene(C₁₋₆),

R₈ and R₉, independently, are alkyl(C₁₋₆), alkenyl or alkinyl(C₃₋₆),cycloalkyl(C₃₋₇), cycloalkylalkyl (C₄₋₈), hydroxyalkyl(C₂₋₆),alkoxyalkyl(C₃₋₆), hydroxyalkoxyalkyl(C₄₋₈), aminoalkyl(C₂₋₆),alkyl(C₁₋₄)aminoalkyl(C₂₋₆), phenyl, phenylalkyl(C₇₋₁₀), or

R₈ and R₉ together with the nitrogen atom form a 5-, 6- or 7-memberedheterocyclic ring, which may contain a further heteromember selectedfrom oxygen, sulphur and a group ═N--R₁₀, wherein R₁₀ is alkyl (C₁₋₄),and

R₆ is hydrogen, halogen, alkyl(C₁₋₄), alkoxy(C₁₋₄), alkylthio(C₁₋₄),alkylsulfonyl(C₁₋₄), trifluoromethyl, nitro, hydroxy, azido, amino,alkyl(C₁₋₄)amino, alkanoyl(C₁₋₅)amino, carbalkoxy(C₂₋₅), aminocarbonyl,trifluoromethoxy, cyano or sulfamyl, and

X is oxygen or sulphur.

In another group of compounds of formula I

R₁ is hydrogen, alkyl(C₁₋₆), alkenyl(C₃₋₆), alkinyl (C₃₋₆),cycloalkyl(C₃₋₇), cycloalkylalkyl(C₄₋₈), phenylalkyl(C₇₋₉) orphenylalkenyl(C₉₋₁₂), the phenyl ring being unsubstituted or mono-, di-or trisubstituted independently by halogen, hydroxy, alkyl(C₁₋₄) oralkoxy(C₁₋₄),

R₂ and R₅, independently, are hydrogen, alkyl(C₁₋₆), phenylalkyl(C₇₋₁₀),cycloalkyl(C₃₋₇) or cycloalkylalkyl(C₄₋₈),

R₃ and R₄, independently, are COR₇ ^(I) or COOR₇ ^(II), wherein R₇ ^(I)is alkyl(C₁₋₆), alkenyl(C₃₋₆), alkinyl(C₃₋₆), cycloalkyl(C₃₋₇),cycloalkylalkyl(C₄₋₈), and R₇ ^(II) is alkyl(C₁₋₆), alkenyl(C₃₋₆),alkinyl(C₃₋₆), cycloalkyl(C₃₋₇), cycloalkylalkyl(C₄₋₈),hydroxyalkyl(C₂₋₆), alkoxyalkyl(C₃₋₆) or hydroxyalkoxyalkyl (C₄₋₈),

R₆ is hydrogen, halogen, alkyl(C₁₋₄), alkoxy(C₁₋₄), alkylthio(C₁₋₄),alkylsulfonyl(C₁₋₄), trifluoromethyl, nitro or hydroxy, and

X is oxygen or sulphur, with the proviso, that at least one of thesubstituents R₂ and R₅ is phenylalkyl (C₇₋₁₀), cycloalkyl(C₃₋₇) orcycloalkylalkyl(C₄₋₈).

A group of compounds are compounds of formula I,

wherein

R₁ is alkyl(C₁₋₆), alkoxyalkyl(C₃₋₆), alkenyl(C₃₋₆), alkinyl(C₃₋₆),cycloalkyl(C₃₋₇),

R₂ and R₅, independently, are hydrogen or alkyl(C₁₋₆),

R₃ and R₄, independently, are COOR₇, wherein R₇ is other thanphenylalkyl.

These compounds show surprisingly beneficial pharmacological activitythan is expected for compounds of this type, e.g. long lasting coronarysufficiency activity in the tests mentioned above and good tolerability.

In another group of formula I

R₁ is alkyl(C₁₋₆), hydroxyalkyl(C₂₋₆), alkoxyalkyl(C₃₋₆), alkenyl(C₃₋₆),alkinyl(C₃₋₆), cycloalkyl(C₃₋₇), cycloalkylalkyl(C₄₋₈), phenylalkyl(C₇₋₉) or phenylalkenyl(C₉₋₁₂), the phenyl ring being unsubstituted ormono-, di- or trisubstituted independently by halogen, hydroxy,alkyl(C₁₋₄) or alkoxy (C₁₋₄),

R₂ and R₅, independently, are hydrogen, alkyl(C₁₋₆), phenylalkyl(C₇₋₁₀),cycloalkyl(C₃₋₇) or cycloalkylalkyl(C₄₋₈),

R₃ and R₄, independently are CN, COR₇, COOR₇, S(O)_(n) R₇ or ##STR89##subject to the proviso as defined above, provided that R₃ and R₄ are notboth COOR₇, wherein R₇ is alkyl(C₁₋₆).

In another group of compounds of formula I

R₁ is alkyl(C₁₋₆), alkenyl(C₃₋₆), alkinyl(C₃₋₆), cycloalkyl(C₃₋₇),

R₂ and R₅, independently, are hydrogen or alkyl(C₁₋₆),

R₃ and R₄, independently, are CN, COR₇, COOR₇, S(O)_(n) R₇ or ##STR90##wherein n, R₇, A, R₈ and R₉ and subject to the proviso as defined aboveand provided that R₃ and R₄ are not both COOR₇, wherein R₇ isalkyl(C₁₋₆).

In a sub-group R₆ is alkylsulfonyl(C₁₋₄), hydroxy, azido, amino,alkyl(C₁₋₄)amino, di[alkyl(C₁₋₄)]amino, alkanoyl(C₁₋₅)amino,aminocarbonyl, tri-fluoromethoxy, sulfamyl, alkyl(C₁₋₄)sulfamyl ordi[alkyl(C₁₋₄)]sulfamyl.

In another group of compounds of formula I R₁ is hydrogen, alkyl(C₁₋₆),hydroxyalkyl(C₂₋₆), alkoxyalkyl(C₃₋₆), alkenyl(C₃₋₆), alkinyl(C₃₋₆),cycloalkyl(C₃₋₇), cycloalkylalkyl(C₄₋₈), phenylalkyl (C₈₋₉) orphenylalkenyl(C₉₋₁₂), the phenyl ring being unsubstituted or mono-, di-or trisubstituted independently by halogen, hydroxy, alkyl(C₁₋₄) oralkoxy (C₁₋₄),

R₂ and R₅, independently, are hydrogen, alkyl(C₁₋₆), phenylalkyl(C₇₋₁₀),cycloalkyl(C₃₋₇) or cycloalkylalkyl(C₄₋₈),

R₃ and R₄, independently are CN, COR₇, COOR₇, S(O)_(n) R₇ or ##STR91##wherein n, R₇, A, R₈ and R₉ and subject to the proviso as defined above,provided that R₃ and R₄ are not independently COR₇, wherein R₇ isalkyl(C₁₋₆), alkenyl(C₃₋₆), alkinyl(C₃₋₆) or COOR₇, wherein R₇ is otherthan phenyl or phenylalkyl as defined above.

In a first group of compounds R₁ is hydrogen.

In a second group of compounds R₁ is alkyl.

In a third group of compounds R₁ is hydroxyalkyl.

In a fourth group of compounds R₁ is alkoxyalkyl.

In a fifth group of compounds R₁ is alkenyl.

In a sixth group of compounds R₁ is alkinyl.

In a seventh group of compounds R₁ is cycloalkyl.

In an eighth group of compounds R₁ is cycloalkylalkyl.

In a ninth group of compounds R₁ is phenylalkyl.

In a tenth group of compounds R₁ is phenylalkenyl.

In an eleventh group of compounds R₂ is alkyl.

In a twelfth group of compounds R₂ is hydrogen.

In a thirteenth group of compounds R₂ is phenylalkyl.

In a fourteenth group of compounds R₂ is cycloalkyl.

In a fifteenth group of compounds R₂ is cycloalkylalkyl.

In a sixteenth group of compounds R₅ is alkyl.

In a seventeenth group of compounds R₅ is hydrogen.

In an eighteenth group of compounds R₅ is phenylalkyl.

In a nineteenth group of compounds R₅ is cycloalkyl.

In a twentieth group of compounds R₅ is cycloalkylalkyl.

In a twentyfirst group of compounds R₅ is identical to R₅.

In a twentysecond group of compounds R₅ is a different radical type fromR₂.

In a twentythird group of compounds R₃ is identical to R₄.

In a twentyfourth group of compounds R₃ is a different radical type fromR₄.

In a twentyfifth group of compounds R₃ ^(I) is a different radical typefrom R₄ ^(I).

In a twentysixth group of compounds R₃ independently is COR₇.

In a twentyseventh group of compounds R₃ independently is COOR₇.

In a twentyeighth group of compounds R₃ independently is SR₇.

In a twentyninth group of compounds R₃ independently is SOR₇.

In a thirtieth group of compounds R₃ independently is SO₂ R₇.

In a thirtyfirst group of compounds R₃ independently is ##STR92##

In a thirtysecond group of compounds R₄ is COR₇.

In a thirtythird group of compounds R₄ is COOR₇.

In a thirtyfourth group of compounds R₄ is SR₇.

In a thirtyfifth group of compounds R₄ is SOR₇.

In a thirtysixth group of compounds R₄ is SO₂ R₇.

In a thirtyseventh group of compounds R₄ is COO--A--NR₈ R₄.

In a thirtyeighth group of compounds R₇ is alkyl.

In a thirtyninth group of compounds R₇ is alkenyl.

In a fourtieth group of compounds R₇ is alkinyl.

In a fourtyfirst group of compounds R₇ is cycloalkyl.

In a fourtysecond group of compounds R₇ is cycloalkyl.

In a fourtythird group of compounds R₇ is cycloalkylalkyl.

In a fourtyfourth group of compounds R₇ is hydroxyalkyl.

In a fourtyfifth group of compounds R₇ is alkoxyalkyl.

In a fourtysixth group of compounds R₇ is hydroxyalkoxyalkyl.

In a fourtyseventh group of compounds R₇ is aminoalkyl.

In a fourtyeighth group of compounds R₇ is alkylaminoalkyl.

In a fourtyninth group of compounds R₇ is di[alkyl]aminoalkyl.

In a fiftieth group of compounds R₇ is phenyl.

In a fiftyfirst group of compounds R₇ is phenylalkyl.

In a fiftysecond group of compounds R₇ is a heterocyclic ring.

In a fiftythird group of compounds R₇ is an alkyl group substituted by aheterocyclic ring.

In a fiftyfourth group of compounds A is ethylene.

In a fiftyfifth group of compounds X is oxygen.

In a fiftysixth group of compounds X is sulphur.

Any of the above groups may be combined to produce e.g. groups whereinthe dihydropyridine substituents in positions 3 and 5, and/or 2 and 6are identical, different or of a different type (e.g. are grouped inseparate groups above).

What we claim is:
 1. A compound having the formula ##STR93## wherein R₁' is hydrogen or C₁₋₆ alkyl;R₂ ' and R₅ ', independently, are hydrogenor C₁₋₆ alkyl; R₃ ' and R₄ ', independently, are COOR₇ ' or ##STR94##each R₇ ', independently, is C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₇₋₁₀phenylalkyl, C₃₋₆ alkoxyalkyl, C₂₋₆ -hydroxyalkyl or C₄₋₈hydroxyalkoxyalkyl; A is C₁₋₆ alkylene; each R₈ ' and R₉ ',independently, is C₁₋₆ alkyl or C₇₋₁₀ phenylalkyl; and X is oxygen orsulphur, with the proviso that at least one of R₃ ' and R₄ ' is COOR₇ 'where R₇ ' is C₂₋₆ hydroxyalkyl or C₄₋₈ hydroxyalkoxyalkyl, or apharmaceutically acceptable acid addition salt of a basic compound ofthe above formula.
 2. A compound of claim 1 wherein R₇ ' is C₂₋₆hydroxyalkyl.
 3. A compound of claim 1 wherein R₇ ' is C₄₋₈hydroxyalkoxyalkyl.
 4. A compound of claim 1 wherein R₁ ' is hydrogen.